tbuckley/cabot-search huggingface dataset:
Abstract 5923: The genetic landscape of metastatic breast cancer reflected in circulating tumor DNA
Authors: Stephanie Kavan
Journal: Cancer Research (2023)

Abstract Tissue biopsies of breast tumors only provide a snapshot of the evolution of the disease and may miss potential therapeutic targets, especially in the metastatic setting. Plasma-derived cell-free tumor DNA constitutes a potential surrogate for tumor DNA obtained from tissue biopsies to potentially capture inter-and intra-tumoral heterogeneity present in metastatic breast cancer. We aimed to investigate to what extent variants identified in the primary tumor and metastases are reflected in plasma. We performed whole-exome sequencing on tumor DNA from primary and metastatic lesions and plasma-derived circulating tumor DNA of eight patients with metastatic breast cancer. Our results show that metastases most often follow parallel evolution, given the low levels of stem mutations detected between primary tumors and matched metastases and mutational events private to the primary tumor. Furthermore, we demonstrated that ctDNA mainly reflected old stem mutations shared between primary tumor and metastasis, and less often, genetic alterations found solely in primary tumor or metastasis. Lastly, clinically relevant variants, e.g., resistance mutations detected in primary tumor and metastasis, were to some extent reflected in ctDNA, including affected genes MET, MTOR, CDK6, PIK3CA, and GATA3. However, mutations in MED1, NCOR1, and NCOR2 were only found in tumor tissues. These findings support the importance of a metastatic deposit biopsy to guide treatment decisions. Together, our results have implications for future ctDNA studies. For monitoring tumor burden using ctDNA, our results suggest that truncal mutations are the best candidates, as they are highest in circulating levels. For confident tracking of subclonal mutations in ctDNA, liquid biopsies are not yet to substitute metastatic tissue biopsies and instead demonstrate support to the current gold standard. Citation Format: Stephanie Kavan. The genetic landscape of metastatic breast cancer reflected in circulating tumor DNA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5923.
Abstract 2720: Enhancing oral delivery of plant-derived vesicles
Authors: Yuan Liu, Adrian Lankenau-Ahumada, Emine Bayraktar, Paul Schwartz, Mamur Chowdhury, Sixiang Shi, Manu M. Sebastian, Htet Khant, Natalia De Val, Zuliang Jie, Nicholas B. Jennings, Cristian Rodriguez-Aguayo, Jody Swain, Elaine Stur, Lingegowda S. Mangala, Yutuan Wu, Supriya Nagaraju, Brooke Erimas, Chun Li, Gabriel Lopez-Berestein, Janet Braam, Anil K. Sood
Journal: Cancer Research (2023)

Abstract Plant-derived vesicles (PDVs) were attractive for therapeutic applications, including as potential nanocarriers. However, a concern with oral delivery of PDVs is whether they would remain intact in the gastrointestinal tract. We found that 82% of cabbage PDVs were destroyed under conditions mimicking the upper digestive tract. To overcome this limitation, we developed a delivery method whereby lyophilized Eudragit S-100-coated cabbage PDVs were packaged into a capsule (Cap-cPDVs). Lyophilization and suspension of PDVs in phosphate-buffered saline did not have an appreciable effect on PDV structure, number of PDVs, or therapeutic effect. However, packaging the lyophilized Eudragit S-100-coated PDVs into capsules allowed them to pass through the upper gastrointestinal tract for delivery into the colon better than did suspension of PDVs in phosphate-buffered saline. Cap-cPDVs demonstrated robust therapeutic effect in a dextran sulfate sodium-induced colitis mouse model. These findings could have broad implications for oral delivery of PDVs. Citation Format: Yuan Liu, Adrian Lankenau-Ahumada, Emine Bayraktar, Paul Schwartz, Mamur Chowdhury, Sixiang Shi, Manu M. Sebastian, Htet Khant, Natalia De Val, Zuliang Jie, Nicholas B. Jennings, Cristian Rodriguez-Aguayo, Jody Swain, Elaine Stur, Lingegowda S. Mangala, Yutuan Wu, Supriya Nagaraju, Brooke Erimas, Chun Li, Gabriel Lopez-Berestein, Janet Braam, Anil K. Sood. Enhancing oral delivery of plant-derived vesicles [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2720.
Abstract 278: Role of ATPIF1 in glioblastoma cell survival and metabolism
Authors: Maheedhara Reddy Guda, Nelli Mnatsakanyan, Daniel Morris, Swapna Asuthkar, Andrew J. Tsung, Kiran Velpula
Journal: Cancer Research (2023)

Abstract The ATPase inhibitory factor 1 (ATPIF1) is a 12 kDa protein that inhibits the mitochondrial F1Fo-ATP synthase in the F1domain. It reverses the mitochondrial ATP synthase complex's function, contributing to the onset of oncogenesis. The overexpression of ATPIF1 in various cancers has recently attracted greater attention; however, its biological significance in human pathology, specifically cancer, remains unknown. Based on immunohistochemistry and Western blot analysis of glioblastoma (GBM) patient specimens, we found ATPIF1 is highly expressed in GBMs. Here we showed that mitochondrial fractions of silencing ATPIF1 in U-87 and U251 cells showed decreased expression of ATPIF1, ATP5A, and ATPG1-G2-G3. Next, we showed that manipulation of ATPIF1 showed increased Reactive Oxygen Species (ROS) and Caspase3/7 activity levels compared to untreated cells. ATPIF1 knockdown further caused cell cycle arrest at the G₀/G1stage, and FITC Annexin V analysis showed increased apoptosis. Increased glucose uptake is associated with aggressive oncological behavior, and here we found elevated levels of TCA metabolites in ATPIF1 knockdown cells. ATPIF1 silenced cells had a shift in extracellular acidification rate, accompanied by a simultaneous increase in proton leak, according to the metabolic analysis performed by Seahorse bio-analyzer. Overall, these observations suggest ATPIF1 plays a key role in the progression of GBM. However, further research is needed to verify the precise mechanisms by which ATPIF1 functions in GBM. Citation Format: Maheedhara Reddy Guda, Nelli Mnatsakanyan, Daniel Morris, Swapna Asuthkar, Andrew J. Tsung, Kiran Velpula. Role of ATPIF1 in glioblastoma cell survival and metabolism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 278.
Abstract 295: Targeting spermine synthase triggers lipid metabolism reprogramming as a new therapeutic option to combat colorectal cancer
Authors: Murong Ma, Yubin Guo, Qing Ye, Pan Deng, Daheng He, Chi Wang, Qing-Bai She
Journal: Cancer Research (2023)

Abstract Dysregulation of polyamine metabolism has been linked to the development of colorectal cancer (CRC). Our recent work demonstrates that spermine synthase (SMS), a polyamine biosynthetic enzyme that converts spermidine to spermine, is overexpressed in CRC, which is required for balancing cellular spermidine levels to facilitate CRC tumorigenesis (Nat Commun 11:3243, 2020). Our findings reveal SMS as an attractive therapeutic target in CRC; yet, genetic depletion of SMS expression only shows a limited antitumor effect. Using unbiased metabolomics and transcriptomics analyses, we identified a lipid metabolism reprograming as among the most impacted metabolic change by SMS depletion in CRC cells. Specifically, SMS depletion significantly altered long-chain fatty acid, triacylglycerol and phospholipid metabolism. Furthermore, targeted inhibition of SMS significantly increased the number of lipid droplets and the levels of long-chain fatty acid acylcarnitines for oxidative phosphorylation in mitochondria, and upregulated expression of genes associated with increased mobilization of polyunsaturated fatty acids and the genes associated with lipid peroxidation for induction of ferroptosis, an iron-dependent form of nonapoptotic cell death. The glutathione peroxidase 4 (GPX4) is a key negative regulator of ferroptosis by neutralizing lipid peroxides. Notably, pharmacological inhibition of GPX4 or its upstream regulator system xc − in combination with genetic depletion or pharmacologic inhibition of SMS synergistically caused lipid peroxidation leading to ferroptosis induction and marked suppression of CRC cell growth. Collectively, these findings highlight lipid metabolism reprograming as an adaptive response to targeted inhibition of SMS to enable CRC cell survival, which represents an Achilles’ heel that can be exploited for potential effective therapy for CRC. Citation Format: Murong Ma, Yubin Guo, Qing Ye, Pan Deng, Daheng He, Chi Wang, Qing-Bai She. Targeting spermine synthase triggers lipid metabolism reprogramming as a new therapeutic option to combat colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 295.
Abstract SY17-03: Age-related changes in the tumor microenvironment drive tumor progression
Authors: Sheila A. Stewart
Journal: Cancer Research (2023)

Abstract Cancer is a disease of the aged. While the accumulation of cell autonomous mutations contributes to tumorigenesis, the central role age-related changes in the tumor microenvironment play in the transformation process is becoming more fully appreciated. Underscoring the importance of an aged microenvironment in cancer development are findings that senescent fibroblasts, which accumulate with age, directly stimulate preneoplastic and neoplastic cell growth and tumor progression. Investigations into how senescent fibroblasts promote tumorigenesis revealed that they express a plethora of growth factors, extracellular matrix remodeling enzymes, chemokines, and cytokines collectively referred to as the senescence associated secretory phenotype (SASP). To identify a role for senescent stromal cells in a spontaneous model of breast cancer, we used single cell RNA-Sequencing (scRNA-Seq) to interrogate the cell types and their functional status in the MMTV-PyMT breast tumor model. This analysis revealed the presence of senescent cancer associated fibroblasts (senCAFs) that we also identified in a human triple negative breast cancer scRNA-Seq database. To establish a role for senCAFs in breast cancer, we mated the PyMT model to the INKATTAC (INK) mouse that allowed us to inducibly eliminate senescent cells. We found that the elimination of senCAFs reduced tumor growth and unleashed the killing power of NK cells. We will discuss the mechanism by which senCAFs impact NK cell killing. Citation Format: Sheila A. Stewart. Age-related changes in the tumor microenvironment drive tumor progression. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr SY17-03.
Abstract 371: Integrin-mediated lipolysis by pancreatic cancer-derived extracellular vesicles in cancer-associated cachexia
Authors: Chikako Shibata, Motoyuki Otsuka, Mitsuhiro Fujishiro
Journal: Cancer Research (2023)

Abstract Introduction: Cancer-associated cachexia (CAC) is a life-threating condition frequently observed in cancer patients, especially those with pancreatic cancer. CAC is a multifactorial disease, with the notable characteristic of systemic lipolysis. Although humoral factors have been implicated in its pathogenesis, critical factors remain to be determined. Since even localized pancreatic cancer frequently induce lipolysis systemically, we examined the molecular mechanisms in vitro and in vivo based on the hypothesis that extracellular vesicles (EVs) systemically released from pancreatic cancer cells induce lipolysis. Procedures: EVs derived from the supernatants of cultured pancreatic cancer cell lines and from the sera of pancreatic cancer patients were characterized. The effects of EVs on adipocytes were determined using mature human adipocytes induced from human adipose-derived mesenchymal stem cells. To confirm the in vitro findings, lipolysis induction was examined in mice by intravenous injection of EVs. EV characteristics inducing lipolysis were determined. Those characteristics were confirmed by knockout studies and examining specifically isolated pancreatic cancer-derived EVs from heterogenous EV population in patients’ sera. Results: Lipolysis was triggered by specific EVs from pancreatic cancer cell line via the cAMP inside and uptake of more EVs into adipocytes was crucial for higher levels of lipolysis. In vivo studies, database search, and knockout studies revealed that integrin β1 and integrin α6 on EVs were the determinants for the attachment and uptake of the EVs to adipocytes, resulting in inducing more lipolysis. There was no difference in the percentage of these integrins positive EVs between heterogenous EV population in cancer patients’ sera and EVs in cancer-free controls’ sera. However, pancreatic cancer cell-derived EVs specifically isolated by targeting CA19-9, an aberrant glycosylation, from heterogenous EV population in patients’ sera, confirmed that pancreatic cancer-derived EVs have more such integrins. Conclusions: Cancer cell-derived EVs in the sera of pancreatic cancer patients have more ITGB1 and ITGA6 levels, which may explain the systemic induction of lipolysis in cancer cachexia from the early stages and could be novel therapeutic targets against CAC. In addition, specific isolation of cancer-derived EVs in sera from heterogenous EV population is crucial for elucidating cancer-related pathogenesis. Citation Format: Chikako Shibata, Motoyuki Otsuka, Mitsuhiro Fujishiro. Integrin-mediated lipolysis by pancreatic cancer-derived extracellular vesicles in cancer-associated cachexia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 371.
Abstract 396: Role of PHF8 in resistance to melanoma targeted therapies
Authors: María de los Ángeles Gómez-Muñoz, Nicole Eskow, Ines Delclaux, Rana Moubarak, Eva Hernando-Monge
Journal: Cancer Research (2023)

Abstract Melanoma is a highly prevalent cancer with increasing incidence worldwide. While immune checkpoint inhibitors have drastically improved outcomes for about half of metastatic melanoma patients, many are still resistant to these treatments or develop life-threatening toxicities. Around 50% of melanomas carry BRAF mutations that result in constitutive activation of the MAPK pathway. Therapeutic combinations of BRAF and MEK inhibitors (MAPKi) have proven very efficient against these tumors, but responses are not durable and treatment-resistant recurrence almost inevitably occurs. Our group recently uncovered a role for the histone demethylase PHF8 in melanoma metastasis, and demonstrated that PHF8 directly controls the expression of key components of the TGFβ pathway. Given that TGFβ signaling crosstalks with the MAPK pathway and contributes to resistance to therapy in various tumors, we decided to investigate a potential role for PHF8 in response and resistance to MAPKi therapy in melanoma. To test our hypothesis, we assessed the effect of modulating PHF8 expression in BRAFV600E-mutant cells and their matched MAPKi-resistant derivatives. PHF8 silencing did not affect cell survival or proliferation of parental, MAPKi-sensitive melanoma cell lines, but it re-sensitized resistant cells to MAPKi treatment. Conversely, PHF8 overexpression in melanoma cell lines did not affect their proliferation rate but increased the emergence of resistant clones in BRAFV600E-mutant melanoma cells treated with BRAFi (Dabrafenib) and MEKi (Trametinib) combinations. Next, we assessed the dynamics of PHF8 expression and TGFβ signaling in melanoma cells exposed to MAPKi. Treatment of MAPKi-sensitive cells leads to a fast and complete downregulation of PHF8 protein expression without a change in mRNA levels, paralleled by reduced TGFβ signaling, as evidenced by decreased SMAD2 phosphorylation. However, PHF8 protein expression is restored in MAPKi resistant clones. Therefore, based on our preliminary data, we postulate that PHF8 suppression by the MAPK pathway plays a critical role in melanoma response to targeted therapy and that its restoration contributes to acquisition of resistance. We are currently investigating MAPK-dependent mechanisms controlling PHF8 stability, and testing novel PHF8 inhibitors for their ability to bypass or overcome melanoma resistance to MAPKi. Our studies might provide basis for a novel epigenetic therapy as a strategy to maximize the potential of MAPKi therapy in melanoma treatment. Citation Format: María de los Ángeles Gómez-Muñoz, Nicole Eskow, Ines Delclaux, Rana Moubarak, Eva Hernando-Monge. Role of PHF8 in resistance to melanoma targeted therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 396.
Abstract SY21-03: Organ-specific responses to targeted and immunotherapies
Authors: Erik Sahai
Journal: Cancer Research (2023)

Abstract The response to treatment of widely disseminated disease can vary depending on the site of metastasis. In some cases, lesions at one site respond to treatment, while disease at other sites continues to grow. This is seen in the context of melanoma treatment with targeted therapy, with some patients having good responses in the liver, while disease in the brain and bone continues apace. This can be attributed to differences in the microenvironment of lesions in different organs, although other factors undoubtedly contribute. It is also increasingly clear that there is an interplay between the site of metastasis and responses to immunotherapy. Liver metastases are particularly difficult to treat compared to other metastatic locations. Moreover, the presence of liver metastases reduces the efficacy of immunotherapy to control disease at other sites in the same patient. Thus, liver metastases confer systemic tolerance. This is likely linked to the liver being a ‘tolerogenic’ organ with a role in modulating the body’s response to commensal bacteria in the gut. To investigate this, we have established an experimental melanoma model of systemic immune tolerance being conferred by liver metastases. We will present results on the mechanism by which liver metastases hinder not only their response to immunotherapy, but also the response of other distant lesions. Citation Format: Erik Sahai. Organ-specific responses to targeted and immunotherapies. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr SY21-03.
Abstract 3963: Mass spectrometry reveals a downregulation of calreticulin after neoadjuvant chemotherapy in pancreatic cancer
Authors: Michael C. Stoffel, Elisabeth BH Dingendorf, Dahlia L. Kittel, Glen Kristiansen, Tristan Lerbs
Journal: Cancer Research (2023)

Abstract Introduction: Pancreatic ductal adenocarcinomas are one of the deadliest cancer types with limited response to current therapies. Thus, this study examined changes in the proteome of epithelial cells in pancreatic cancer after neoadjuvant chemotherapy with gemcitabine, to identify new therapeutic targets. Methods: Upon receiving patient consent, fresh pancreatic cancer tissue was received from surgical tumor resections at the University Hospital of Bonn. We mechanically and enzymatically digested and purified the tissue to create single-cell suspensions. After staining the cells against CD45 und CD326, we purified epithelial cells, blood cells, and stroma through FACS. To analyze their proteome, the sorted cells were lysed in TEAB buffer and the protein lysates were measured by the mass spectrometry core facility at the University of Bonn. We then analyzed the data using DAVID and Shiny GO. Results: Gene enrichment analyses showed a significantly reduced expression of calreticulin after neoadjuvant chemotherapy in epithelial cells. A direct comparison between untreated and treated epithelium cancer cells using a heat map showed a decreased expression of actin and enzymes of glycolysis in treated cancer cells. Moreover, untreated epithelial cells showed an increase of proteins related to MHC class Ib protein complex assembly and antigen processing and presentation of endogenous peptide antigen via MHC class. In contrast, treated cells showed a higher presence of proteins for nutrient supply from the blood. Furthermore, untreated stroma cells exhibited an increased number of proteins responsible for mesenchymal migration and for actin filament fragmentation. Conclusion: This study shows that neoadjuvant chemotherapy with gemcitabine leads to distinct changes in the proteome of tumor cells in pancreatic cancers. In particular, a decreased expression of the “eat-me-signal” calreticulin impairs macrophage-mediated cancer cell phagocytosis, thereby indicating a mechanism by which cancer cells protect themselves after chemotherapy. Citation Format: Michael C. Stoffel, Elisabeth BH Dingendorf, Dahlia L. Kittel, Glen Kristiansen, Tristan Lerbs. Mass spectrometry reveals a downregulation of calreticulin after neoadjuvant chemotherapy in pancreatic cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3963.
Abstract PL05-03: What if all your favorite proteins are druggable
Authors: Gregory R. Bowman
Journal: Cancer Research (2023)

Abstract Many proteins that play key roles in cancer are considered difficult drug targets, if not entirely undruggable, due to an apparent lack of pockets where small molecules can bind with the affinity and specificity required for a drug. ‘Cryptic’ pockets that are absent in known structures of proteins but form due to protein dynamics could alleviate this problem. However, it has been hard to assess or exploit the opportunities that cryptic pockets present due to the inherent difficulty in identifying such pockets. Here, I will discuss progress from my lab on combining biophysical experiments, computer simulations, and machine learning to identify and target cryptic pockets. In one case study, we have used computer simulations deployed on the Folding@home distributed computing environment to predict a cryptic pocket that can allosterically control a protein-RNA interaction, and then experimentally confirmed our predictions. Based on data from this study and others in our lab, we have trained a machine learning algorithm to predict where cryptic pockets are likely to form from single protein structures, enabling us to assess how prevalent cryptic pockets are on a large scale. Citation Format: Gregory R. Bowman. What if all your favorite proteins are druggable. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr PL05-03.